Cancers severely imperil health and life of human, which have become the second cause of death only except cardiovascular diseases (CVDs), lead to death beyond the sum of acquired immune deficiency syndrome (AIDS) and tuberculosis and malaria, and the incidence rate thereof increases yearly. It is expected that the number of cancer patients around the world would exceed 26 million, and the number of death thereof would reach 17 million in 2030. Nowadays, chemotherapy has been one of effective methods for the treatment of tumor. In recent years, the tumor chemotherapy has achieved remarkable progresses, prolonging cancer patients' survival time significantly, especially the breakthrough for the treatment of leukemia, malignant lymphoma and so forth. However, for solid tumors that account for more than 90% of malignant tumors and are harmful to human life and health seriously, the treatment does not achieve satisfactory results. Therefore, the research and development of new antitumor drugs have become an urgent need.
Artemisinin is a sesquiterpene lactone with a peroxide bridge structure, which is isolated from Chinese medicinal plant Artemisia annua L., and extensively used as an antimalarial drug. Then, the researchers modified artemisinin and obtained dihydroartemisinin, artesunate, artemether arteether, etc., all of which have a stronger resistance to malaria with fewer side effects. Studies in recent years have found that artemisinin and its derivatives also have other various pharmacological effects, such as anti-tumor anti-virus, anti-inflammatory, immune regulation effects, etc. Among them, the studies on antitumor activity of artemisinin and its derivatives have received a widespread attention. Artemisinin and its derivatives have certain inhibitory or killing effect for variety of tumor cells, including leukemia, breast cancer, cervical cancer, ovarian cancer, stomach cancer, colon cancer, liver cancer, pancreatic cancer, lung cancer, osteosarcoma, etc., and almost have no influence on normal cells at a therapeutic concentration. Such mechanism for killing tumor cells is possibly by ways of inducing apoptosis in tumor cells, inhibiting proliferation of tumor cells and inhibiting tumor angiogenesis, reversing multi-drug resistance, and the like. At the same time, studies have found that artemisinin compounds have no cross-resistance with the traditional chemotherapy drugs, and can reverse the multi-drug, resistance of tumor cells. Artemisinin is interested by people, and thus has become a potential lead compound of new anti-cancer drugs with high efficacy and low toxicity.
In view of above, the present inventors have designed and synthesized a series of nitrogen-containing heterocyclic ring substituted dihydroartemisinin derivatives, and the results of antitumor activity in vitro screening tests have showed that such synthesized compounds have a good antitumor activity.